Caffey disease: an unlikely collagenopathy Francis H. Glorieux J Clin Invest. 2005;115(5):1142-1144. https://doi.org/10.1172/JCI25148. Commentary Infantile cortical hyperostosis (also known as Caffey disease) is characterized by hyperirritability, acute inflammation of soft tissues, and profound alterations of the shape and structure of the underlying bones, particularly the long bones, mandible, clavicles, or ribs. In this issue of the JCI, Gensure et al. undertook fine mapping of the genetic locus for this disease in a large kindred of individuals with the autosomal dominant form of the condition. The authors found a novel missense mutation in COL1A1, the gene encoding the α1 chain of type I collagen, in all affected individuals in 3 discrete pedigrees. This is a surprising finding, as all other reported mutations affecting the synthesis of type I collagen lead to conditions such as osteogenesis imperfecta and Ehlers-Danlos syndrome, in which quantitative or qualitative defects in type I collagen synthesis give rise to bone fragility and/or connective tissue hyperextensibility. The deleterious effect of the mutation on collagen fibril morphology is demonstrated; however, the precise functional link between the reported missense mutation and the localized inflammation and hyperostosis seen in Caffey disease awaits future studies. Find the latest version: https://jci.me/25148/pdf commentaries apolipoprotein B-100 in NIDDM. Diabetologia. 120:1183–1192. 17. Schattenberg, J.M., Wang, Y., Singh, R., Rigoli, 38:959–967. 16. Powell, E.E., et al. 1990. The natural history of R.M., and Czaja, M.J. 2005. Hepatocyte CYP2E1 15. Sanyal, A.J., et al. 2001. Nonalcoholic steato- nonalcoholic steatohepatitis: a follow-up study of overexpression and steatohepatitis lead to hepatitis: association of insulin resistance and forty-two patients for up to 21 years. Hepatology. impaired hepatic insulin signaling. J. Biol. Chem. mitochondrial abnormalities. Gastroenterology. 11:74–80. 280:9887–9894. Caffey disease: an unlikely collagenopathy Francis H. Glorieux Departments of Surgery, Pediatrics, and Human Genetics, McGill University, and Genetics Unit, Shriners Hospital for Children, Montréal, Quebec, Canada. Infantile cortical hyperostosis (also known as Caffey disease) is character- Bone lesions ized by hyperirritability, acute inflammation of soft tissues, and profound The radiographic features of ICH evolve alterations of the shape and structure of the underlying bones, particularly in stages. Hyperostoses develop on the the long bones, mandible, clavicles, or ribs. In this issue of the JCI, Gensure outer cortical surface, expand, and then et al. undertook fine mapping of the genetic locus for this disease in a large remodel by resorption either at the exter- kindred of individuals with the autosomal dominant form of the condition. nal surface or at the endocortical surface. The authors found a novel missense mutation in COL1A1, the gene encod- In the latter case, there is an expansion of ing the α1 chain of type I collagen, in all affected individuals in 3 discrete the medullary cavity and the cortex is thin pedigrees (see the related article beginning on page 1250). This is a surpris- (Figure 2B). Epiphyses and metaphyses are ing finding, as all other reported mutations affecting the synthesis of type I typically not involved. Tubular bones may collagen lead to conditions such as osteogenesis imperfecta and Ehlers-Dan- be grossly deformed (Figure 1), with bony los syndrome, in which quantitative or qualitative defects in type I collagen bridges sometimes appearing between synthesis give rise to bone fragility and/or connective tissue hyperextensi- adjacent bones (forearm, ribs). The histol- bility. The deleterious effect of the mutation on collagen fibril morphology ogy of the bone lesions has been described is demonstrated; however, the precise functional link between the reported in detail (3). Such lesions include not only missense mutation and the localized inflammation and hyperostosis seen in subperiosteal new lamellar bone forma- Caffey disease awaits future studies. tion but also evidence of local inflamma- tion. Early on, foci of acute inflammation Infantile cortical hyperostosis (ICH) note that this phase of acute inflamma- are confined in the periosteum; they then — also referred to as Caffey or Caffey-Sil- tion precedes the abnormal thickening of disrupt the periosteal envelope to blend verman disease — was recognized in 1945 cortical bone (hyperostosis) that gives its with contiguous tissues (fasciae, muscle, by Caffey and Silverman (1). The condi- name to the disease. It also subsides long and tendon). In the subacute phase, the tion, later shown to be transmitted as an before the hyperostosis resolves. Some- periosteum reestablishes itself as an entity autosomal dominant trait with incom- times lesions recur suddenly in their orig- with a sheet of fibrous tissue under which plete penetrance, becomes clinically evi- inal sites or in new sites, either during or new subperiosteal bone is formed. In the dent before 5–7 months of life, and the after the subsidence of the swellings that late remodeling stage, signs of inflam- average age at onset is around 9 weeks. appeared at the onset of the disease. This mation disappear, and excess peripheral The initial symptom is general hyperirri- uneven protracted clinical course with bone is removed. tability, with fever and anorexia, quickly unpredictable remissions and relapses is Based on these facts, discussion of the followed by painful, firm soft-tissue one of the most characteristic features of pathophysiology of ICH naturally turns swelling, particularly in the face (cheeks the condition (2). toward a mechanism likely to induce and jaws), the scapular region, and upper and lower limbs. It is usually self-lim- ited, with severe symptoms lasting from 2–3 weeks to 2–3 months. The pattern of distribution of the lesions varies from patient to patient and can be symmetri- cal (Figure 1). Swelling also involves underlying muscle. It is important to Nonstandard abbreviations used: COL1A1, gene encoding the α1 chain of type I collagen; EDS, Ehlers- Danlos syndrome; ICH, infantile cortical hyperostosis; PGE, prostaglandin E. Conflict of interest: The author has declared that no Figure 1 conflict of interest exists. A 6-month-old girl with typical clinical findings of Caffey disease, which appeared at age 7 Citation for this article: J. Clin. Invest. 115:1142–1144 weeks. The painful swelling of soft tissue around the legs (A) is matched by severe involvement (2005). doi:10.1172/JCI200525148. of the tibia and fibula bilaterally (x-radiography, B). Femurs are strikingly unaffected. 1142 The Journal of Clinical Investigation http://www.jci.org Volume 115 Number 5 May 2005 commentaries Figure 2 Schematic illustrating normal and exuberant bone formation. (A) Representation of a growing bone. Growth in length is achieved by endochondral bone formation adding cancellous bone in the metaphyseal area. Gain in diameter comes from subperiosteal new bone apposition by intramem- branous bone formation. The periosteum is an envelope of fibrous connective tissue that is wrapped around diaphyses. The size of the marrow cavity is controlled by a combination of bone apposition and resorption at the endocortical surface. (B and C) In ICH/Caffey disease, hyperostosis develops by exacerbated subperiosteal intramembranous bone formation triggered by local inflammation (left side of B and C). In the remodeling phase, the excess of bone tissue is resorbed either at the endocortical surface, leading to an expansion of the marrow cavity and a more persistent deformity (right side of B), or at the exocortical surface, with no effect on the size of the marrow cavity (right side of C). local inflammation. Such a hypothesis collagen (6). The careful and elegant work the triple-helical domain. Because of its received strong support from a report by of Gensure et al. has established a strong small size, it packs tightly at the center of Ueda et al. (4) demonstrating that admin- linkage between the ICH phenotype and the helix and confers stability. A mutation istration of prostaglandin E (PGE) in the COL1A1 locus on chromosome 17q21 affecting a Gly residue will thus have an infants with ductus-dependent cyanotic in 3 discrete pedigrees from Australia and impact on the conformation of the colla- heart disease induced a form of cortical Canada with an autosomal dominant gen molecule, its integration in the tissue hyperostosis that mimics ICH. Two years form of ICH. More importantly, despite (bone, skin, and tendon), and the struc- later, Heyman et al. (5) reported that in 5 the fact that the families were geographi- tural qualities of the tissue. This is the affected children, PGE serum levels were cally dispersed and unrelated, it was case in osteogenesis imperfecta, or brittle significantly elevated and that treatment found that all affected individuals were bone disease, where most mutations with- with indomethacin (an inhibitor of PGE heterozygous for the identical mutation, in COL1A1 are glycine substitutions. The synthesis) rapidly suppressed irritabil- a substitution of Arg by Cys at position severity of the phenotype is determined ity and led to a progressive decrease in 836 (R836C), within the helical domain in part by the pattern of inheritance, the soft-tissue swelling in 6–9 days. Wheth- of the α1 chain of type I collagen. The position of the mutation in the α1 chain, er elevated PGE levels were a cause or a linkage and sequencing data are solid and and the bulkiness of the replacement resi- consequence of the lesions could not be convincing and represent a major step for- due, as it will variably compromise forma- answered. We have made the same obser- ward in the understanding of the pathol- tion and stability of the helix. vations in 3 patients (Glorieux et al., ogy of an elusive disease. In contrast, the R836C mutation iden- unpublished data). One has to now try and understand how tified by Gensure et al. (6) in these ICH a point mutation in a widely distributed patients would not be predicted to have ICH pathophysiology structural protein can initiate the cascade such an effect on the collagen molecule.